Bioartificial pancreas

ABSTRACT

A bioartificial device, such as a bioartificial pancreas, for implantation in a patient&#39;s vascular system. The bioartificial pancreas includes a scaffold adapted to engage an interior wall of a blood vessel, a cellular complex support by the scaffold and extending longitudinally within the interior cavity of the scaffold so as to be exposed to the blood flow when the scaffold is engaged with the blood vessel, the cellular complex support comprising one or more pockets bordered by thin film; and cellular complex comprising pancreatic islets disposed in the one or more pockets, the thin film being adapted to permit oxygen and glucose to diffuse from flowing blood into the one or more pockets at a rate sufficient to support the viability of the islets. The invention also includes methods of making and using a bioartificial pancreas.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Application No. 62/907,434,filed Sep. 27, 2019, which is herein incorporated by reference in itsentirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety to the sameextent as if each individual publication or patent application wasspecifically and individually indicated to be incorporated by reference.

FIELD

Described herein are intravascular bioartificial devices having atubular geometry. In particular embodiments, the intravascularbioartificial device is bio-absorbable and includes a cellular complexof cells and a biocompatible material. In some embodiments, the cellsare within pancreatic islets.

BACKGROUND

Type 1 diabetes is a chronic metabolic disorder characterized by thebody's inability to produce adequate amounts of insulin for regulatingblood sugar. Type 1 diabetes accounts for roughly 10% of the greaterthan 420 million global cases of diabetes. Although the cause of type 1diabetes is unknown, it is believed that an underlying mechanisminvolves autoimmune destruction of insulin-producing beta cells in thepancreas. If left untreated, complications related to high blood sugarcan include damage to blood vessels, nerves and organs, seizures,diabetic ketoacidosis, and even death. Thus, people with Type 1 diabetesare traditionally insulin-dependent for life. Insulin treatmenttypically involves the use of syringes or insulin pumps to deliverinsulin intravenously. However, daily insulin treatments are not alwaysable to precisely and continuously meet the demands of the uncontrolledvariations in stress, food intake, and physical activity levels.

Alternative treatments include pancreatic islet transplantation as a wayto reduce the rigorous blood glucose monitoring and provide a morereliable means for generating and delivering insulin. Recent advanceshave provided the development of the bioartificial pancreas, whichgenerally involves encapsulation of pancreatic islets in asemi-permeable environment to allow oxygen and glucose to reach thecells within the islets and to remove insulin and waste products fromthe cells. Although various kinds of bioartificial pancreases have beendeveloped, many of these approaches have been found to have limitations.

What is needed, therefore, is an improved bioartificial pancreas andmethods of treating and managing diabetes and other metabolic disorders.

SUMMARY

Described herein are bioartificial implants, such as bioartificialpancreas implants, that can provide automatic and continuous regulationof hormones, such as insulin, for a patient. The term “bioartificial”refers to the implant being composed of both living and manufacturedcomponents. The implant can include a cellular complex, which includes acombination of living cells and one or more biocompatible materials forsustaining the viability of the cells. In some cases, the cells aredispersed within a matrix of the biocompatible material. The cells maybe encapsulated within the biocompatible material so that thebiocompatible material can act as a semi-permeable immune barrier. Whenimplanted within the patient's body, the cells can produce one or morehormones to modulate the patient's endocrine system. For example, thecells may secrete insulin and/or glucagon for modulating blood glucoselevels within the patient's blood. The cells participate in a feedbacksystem with the body to regulate the glucose levels based on hormonelevels in the blood stream.

According to some embodiments, the cellular complex can be formed intoor loaded onto a tubular shaped structure, such as a stent. The size andshape of the tubular structure can be configured for insertion withinthe patient's blood vessel while the biocompatible material can maintainthe viability of the cells. The tubular shaped implant may be expandablesuch that the implant can be inserted within the patient's blood vesselwhile in a collapsed state and expanded at a target location within theblood vessel. When deployed, an outer wall of the tubular shaped implantmay be secured against the blood vessel wall. By placing the implantclose to the patient's blood stream, the cells can receive adequateoxygenation and nutrient support, and hormones generated by the cellsmay quickly enter the patient's blood stream.

In some cases, the bioartificial implant is configured to promoteformation of a layer of endothelial cells over the implant, which mayalso act as a semi-permeable immune barrier. The implant can becomeencased within a pocket between the layer of endothelial cells and theblood vessel wall, which also can serve to protect the cells from thepatient's immune system.

The implant may optionally be made of one or more bio-absorbable (alsoreferred to as bioresorbable) materials that gradually degrade andbecome absorbed in the body. For example, the stent may be composed of abio-absorbable polymer or metal, and the biocompatible material thatsupports and sustains the viability of the cells may also be composed ofa bio-absorbable polymer. Thus, once the cells deteriorate or no longerproduce hormones, the implant can become absorbed by the patient's body,making it unnecessary to retrieve the implant from the patient's body.After the implant is absorbed and cleared from the body, one or moreadditional implants may be inserted into the patient as needed.

Any of the bioartificial implants described herein can be used to treatone or more diseases or conditions. In some cases, the implant is usedto treat a patient suffering from a metabolic disorder, such as type 1diabetes. However, use of the implants is not limited to treating anyparticular type of metabolic disorder or to metabolic disorders ingeneral. For example, the implant can be composed of pancreatic isletswhich may generate insulin, glucagon, amylin, somatostatin, ghrelin,and/or pancreatic polypeptides in any combination and ratio.Alternatively or additionally, the implant can be composed of thyroidhormone producing cells, parathyroid producing cells, adrenal-hormoneproducing cells (e.g., cortisol). Alternatively or additionally, theimplant can be composed of non-cellular particles composed ofchemotherapeutics and biologic drugs.

According to some embodiments, a bioartificial pancreas implant forplacement within a patient's blood vessel includes: a stent having anouter surface defining a diameter sufficiently small for placementwithin the patient's blood vessel and an inner surface defining a lumenfor blood to flow therethrough; and a cellular complex covering at leasta portion of the inner and outer surfaces of the stent, the cellularcomplex comprising pancreatic islet cells and one or more biocompatiblematerials for sustaining viability of the pancreatic islet cells. Thestent can be a bio-absorbable stent. The stent can include a number ofstruts, wherein the cellular complex covers at least a portion of thestruts. The pancreatic islet cells may be embedded within pores of amatrix of the one or more biocompatible materials. The pancreatic isletcells may be dispersed within a matrix of the one or more biocompatiblematerials. The one or more biocompatible materials may bebio-absorbable. The bio-absorbable stent can include a bio-absorbablematerial having a resorption rate ranging from about 3 months to about 3years. The bio-absorbable stent may include a bio-absorbable polymerand/or a bio-absorbable metal. The cellular complex can include one ormore external layers of biocompatible material to fully encapsulate thepancreatic islet cells. A tubular wall of the bio-absorbable stent mayinclude one or more blood flow pathways for oxygenating the blood vesseland promoting neovascularization of the pancreatic islet cells. Thetubular wall may include a number of struts separated by spaces, wherethe blood flow pathways correspond to the spaces between the struts. Theimplant can include one or more chemical agents such as a growth factorand/or an anticoagulant. The cellular complex may include from about50,000 and one million pancreatic islet cells. The implant may beconfigured to promote growth of endothelial cells between the patient'sblood stream and the implant. The implant may include a semipermeablemembrane that surrounds the bio-absorbable stent, the cellular complex,and the cells, where the semipermeable membrane is configured tosubstantially prevent exposure of the pancreatic islet cells to thepatient's immune response and to allow permeation of hormones, oxygen,nutrients, and waste products.

According to some embodiments, a bioartificial pancreas implant forplacement within a patient's blood vessel includes: a bio-absorbablematerial having pancreatic islets dispersed therein and configured tosustain a viability of the pancreatic islets, wherein the islets areencapsulated within the bio-absorbable material, wherein thebio-absorbable material has a tubular shape including an outer surfaceconfigured to contact the patient's blood vessel and an inner surfacedefining a lumen for blood to flow therethrough. The tubular shapedbio-absorbable material may have a diameter substantially the same as aninner diameter of the patient's blood vessel. The tubular shapedbio-absorbable material may include wall having a mesh-like structurewith a number of holes. The implant can be configured to promote growthof endothelial cells between the patient's blood stream and thebio-absorbable material. The pancreatic islet cells can be embeddedwithin pores of a matrix of the bio-absorbable material. Thebio-absorbable material can include one or more polymer materials. Thebio-absorbable material may include one or more external layers ofbio-absorbable material to fully encapsulate the pancreatic islets. Awall of the tubular shaped bio-absorbable material may include one ormore blood flow pathways for oxygenating the blood vessel and promotingneovascularization of the pancreatic islets. The one or more blood flowpathways may include openings within the walls of the tubular shapedbio-absorbable material. The implant can have a concentration ofpancreatic islets ranging from about 5% and about 99% by weight.

According to some embodiments, a method of forming a bioartificialpancreas implant includes: forming a cellular complex by mixingpancreatic islets with one or more biocompatible materials, the one ormore biocompatible materials configured to sustain a viability of thepancreatic islets; and coating at least a portion of a stent(optionally, a bio-absorbable stent) with the cellular complex, whereinat least a portion of the pancreatic islets become encapsulated by thebiocompatible material. The method can further include coating thecellular complex with one or more layers of the one or morebiocompatible materials to fully encapsulate the islets. Coating thestent with the cellular complex may involve a liquid deposition process,an ultrasonic coating process, or a combination of liquid deposition andultrasonic coating processes. The stent may include a tubular wallhaving a number of struts separated by spaces, where coating the stentincludes covering at least a portion of the struts. A concentration ofthe pancreatic islets in the cellular complex ranges from about 5% andabout 99%.

According to some embodiments, a method of treating a patient sufferingfrom diabetes includes: inserting the implant into the patient's bloodvessel, wherein the implant comprises a bio-absorbable stent coveredwith a cellular complex comprising pancreatic islets and one or morebiocompatible materials for sustaining viability of the pancreaticislets, wherein the bio-absorbable stent is in a contracted state duringthe inserting; and expanding the bio-absorbable stent at a targetlocation in the patient's blood vessel such that the implant contactsvessel walls of the blood vessel.

Another aspect of the invention provides a bioartificial pancreas with ascaffold adapted to engage an interior wall of a blood vessel, thescaffold having a blood flow lumen extending longitudinally through aninterior cavity of the scaffold so as to permit blood flow therethroughwhen the scaffold is engaged with the blood vessel; a cellular complexsupport by the scaffold and extending longitudinally within the interiorcavity of the scaffold so as to be exposed to the blood flow when thescaffold is engaged with the blood vessel, the cellular complex supporthaving one or more pockets bordered by thin film; and cellular complexincluding but not limited to pancreatic islets disposed in the one ormore pockets, the thin film being adapted to permit oxygen and glucoseto diffuse from flowing blood into the one or more pockets at a ratesufficient to support the viability of the islets.

In some embodiments of the bioartificial pancreas according to thisaspect, the cellular complex support has a thickness from 0.30 mm to 1.0mm when loaded with the cellular complex. In some or all of theseembodiments, the cellular complex support may also have an attachmentregion adjacent the one or more pockets, the cellular complex supportbeing attached to the scaffold at the attachment region. In suchembodiments, the bioartificial pancreas may also include a thermal bondbetween the attachment region and the scaffold attaching the cellularcomplex support to the scaffold, a suture attaching the cellular complexsupport to the scaffold, and/or a pressure bond between the attachmentregion and the scaffold attaching the cellular complex support to thescaffold. The cellular complex support may also include a plurality ofattachment regions adjacent a plurality of pockets, with cellularcomplex including but not limited to pancreatic islets disposed in theone or more pockets each of the pockets.

In some or all of these embodiments, the cellular complex support hastwo microporous thin film layers. Each microporous layer may have, e.g.,a plurality of pores each having a diameter less than 100 μm, and eachmicroporous layer may have a thickness less than 0.1 mm.

In some or all of these embodiments, the cellular complex may have anislet density of 2.5% to 100%, e.g., 12% to 30%.

In some embodiments, the cellular complex support extends substantiallyaround the interior cavity, and in some embodiments the cellular complexsupport extends only partially around the interior cavity.

In some embodiments, the scaffold is an expandable stent. In suchembodiments the cellular complex support may be attached to struts ofthe expandable stent.

In some or all of these embodiments, the scaffold and cellular complexsupport have a delivery configuration with a first diameter and adeployed configuration with a second diameter greater than the firstdiameter, the bioartificial pancreas being adapted to be delivered inthe delivery configuration by a catheter to an implantation site withinthe blood vessel and to be expanded to the deployed configurationoutside of the catheter at the implantation site. In some or all ofthese embodiments, the scaffold may be bio-absorbable.

Yet another aspect of the invention provides a bioartificial pancreasincluding a scaffold adapted to engage an interior wall of a bloodvessel, the scaffold having a blood flow lumen extending longitudinallythrough an interior cavity of the scaffold so as to permit blood flowtherethrough when the scaffold is engaged with the blood vessel; acellular complex support supported by the scaffold and extendinglongitudinally within the interior cavity of the scaffold so as to beexposed to the blood flow when the scaffold is engaged with the bloodvessel, the cellular complex support having a plurality of sealedpockets and a plurality of attachment regions attached to the scaffold;and cellular complex with pancreatic islets disposed in the sealedpockets, the cellular complex support being adapted to permit oxygen andglucose to diffuse from flowing blood into the sealed pockets at a ratesufficient to support the viability of the islets. The cellular complexsupport may have a thickness from 0.30 mm to 1.0 mm when loaded with thecellular complex.

Embodiments of the bioartificial pancreas according to this aspect mayalso include a thermal bond between one or more of the attachmentregions and the scaffold attaching the cellular complex support to thescaffold, one or more sutures attaching the cellular complex support tothe scaffold, and/or a pressure bond between one or more of theattachment regions and the scaffold attaching the cellular complexsupport to the scaffold.

In some or all of these embodiments, the cellular complex support hastwo microporous thin film layers. Each microporous layer may have, e.g.,a plurality of pores each having a diameter less than 100 μm, and eachmicroporous layer may have a thickness less than 0.1 mm.

In some or all of these embodiments, the cellular complex may have anislet density of 2.5% to 100%, e.g., 12% to 30%.

In some embodiments, the cellular complex support extends substantiallyaround the interior cavity, and in some embodiments the cellular complexsupport extends only partially around the interior cavity.

In some embodiments, the scaffold is an expandable stent. In suchembodiments the cellular complex support may be attached to struts ofthe expandable stent.

In some or all of these embodiments, the scaffold and cellular complexsupport have a delivery configuration with a first diameter and adeployed configuration with a second diameter greater than the firstdiameter, the bioartificial pancreas being adapted to be delivered inthe delivery configuration by a catheter to an implantation site withinthe blood vessel and to be expanded to the deployed configurationoutside of the catheter at the implantation site. In some or all ofthese embodiments, the scaffold may be bio-absorbable.

Still another aspect of the invention provides a bioartificial pancreasincluding a scaffold adapted to engage an interior wall of a bloodvessel, the scaffold having a blood flow lumen extending longitudinallythrough an interior cavity of the scaffold so as to permit blood flowtherethrough when the scaffold is engaged with the blood vessel; acellular complex support supported by the scaffold and extendinglongitudinally within the interior cavity of the scaffold so as to beexposed to the blood flow when the scaffold is engaged with the bloodvessel, the cellular complex support having one or more pockets; andcellular complex with pancreatic islets disposed in the one or morepockets; wherein the cellular complex support has a thickness from 0.30mm to 1.0 mm when loaded with the cellular complex.

In one embodiment, the cellular complex support also has an attachmentregion adjacent the one or more pockets, the cellular complex supportbeing attached to the scaffold at the attachment region. In suchembodiments, the bioartificial pancreas may also include a thermal bondbetween the attachment region and the scaffold attaching the cellularcomplex support to the scaffold, a suture attaching the cellular complexsupport to the scaffold, and/or a pressure bond between the attachmentregion and the scaffold attaching the cellular complex support to thescaffold. The cellular complex support may also include a plurality ofattachment regions adjacent a plurality of pockets, with cellularcomplex including but not limited to pancreatic islets disposed in theone or more pockets each of the pockets.

In some or all of these embodiments, the cellular complex support hastwo microporous thin film layers. Each microporous layer may have, e.g.,a plurality of pores each having a diameter less than 100 μm, and eachmicroporous layer may have a thickness less than 0.1 mm.

In some or all of these embodiments, the cellular complex may have anislet density of 2.5% to 100%, e.g., 12% to 30%.

In some embodiments, the cellular complex support extends substantiallyaround the interior cavity, and in some embodiments the cellular complexsupport extends only partially around the interior cavity.

In some embodiments, the scaffold is an expandable stent. In suchembodiments the cellular complex support may be attached to struts ofthe expandable stent.

In some or all of these embodiments, the scaffold and cellular complexsupport have a delivery configuration with a first diameter and adeployed configuration with a second diameter greater than the firstdiameter, the bioartificial pancreas being adapted to be delivered inthe delivery configuration by a catheter to an implantation site withinthe blood vessel and to be expanded to the deployed configurationoutside of the catheter at the implantation site. In some or all ofthese embodiments, the scaffold may be bio-absorbable.

Yet another aspect of the invention provides a bioartificial pancreasincluding: a scaffold adapted to engage an interior wall of a bloodvessel, the scaffold having a blood flow lumen extending longitudinallythrough an interior cavity of the scaffold so as to permit blood flowtherethrough when the scaffold is engaged with the blood vessel; acellular complex support with a thin film supported by the scaffold andextending longitudinally within the interior cavity of the scaffold soas to be exposed to the blood flow when the scaffold is engaged with theblood vessel, the cellular complex support comprising and one or morepockets bordered by two microporous thin film layers, the thin filmlayers having a thickness less than 0.1 mm and a plurality of pores eachhaving a diameter less than 100 μm; and cellular complex with pancreaticislets disposed in the one or more pockets.

In some or all of these embodiments, the cellular complex support mayalso have an attachment region adjacent the one or more pockets, thecellular complex support being attached to the scaffold at theattachment region. In such embodiments, the bioartificial pancreas mayalso include a thermal bond between the attachment region and thescaffold attaching the cellular complex support to the scaffold, asuture attaching the cellular complex support to the scaffold, and/or apressure bond between the attachment region and the scaffold attachingthe cellular complex support to the scaffold. The cellular complexsupport may also include a plurality of attachment regions adjacent aplurality of pockets, with cellular complex including but not limited topancreatic islets disposed in the one or more pockets each of thepockets.

In some or all of these embodiments, the cellular complex support hastwo microporous thin film layers. Each microporous layer may have, e.g.,a plurality of pores each having a diameter less than 100 μm, and eachmicroporous layer may have a thickness less than 0.1 mm.

In some or all of these embodiments, the cellular complex may have anislet density of 2.5% to 100%, e.g., 12% to 30%.

In some embodiments, the cellular complex support extends substantiallyaround the interior cavity, and in some embodiments the cellular complexsupport extends only partially around the interior cavity.

In some embodiments, the scaffold is an expandable stent. In suchembodiments the cellular complex support may be attached to struts ofthe expandable stent.

In some or all of these embodiments, the scaffold and cellular complexsupport have a delivery configuration with a first diameter and adeployed configuration with a second diameter greater than the firstdiameter, the bioartificial pancreas being adapted to be delivered inthe delivery configuration by a catheter to an implantation site withinthe blood vessel and to be expanded to the deployed configurationoutside of the catheter at the implantation site.

Another aspect of the invention provides a method of preparing abioartificial pancreas, the bioartificial pancreas having a scaffold anda cellular complex support. Some embodiments of the method include thefollowing steps: injecting cellular complex through an opening into apocket of the cellular complex support, the cellular complex includingpancreatic islets; and closing the opening.

In some embodiments, the injecting step includes the step of injectingthe cellular complex through a tube extending through the opening. Someembodiments include the additional step of withdrawing the tube, e.g.,by optionally withdrawing the tube while injecting the cellular complex.

Some embodiments include the step of attaching the cellular complexsupport to the scaffold, e.g., before or after the step of injectingcellular complex into the pocket of the cellular complex support.

In embodiments in which the cellular complex support also has aplurality of pockets and a plurality of attachment regions, theinjecting step may also include the step of injecting cellular complexinto the plurality of pockets, and the attaching step may include thestep of attaching the attachment regions to the scaffold.

Yet another aspect of the invention provides a method of treating apatient suffering from diabetes. In some embodiments, the methodincludes the steps of: implanting a bioartificial pancreas at animplantation site in a blood vessel of the patient, the bioartificialpancreas having a cellular complex support and a cellular complexdisposed within the cellular complex support, the cellular complexincluding pancreatic islets; permitting blood to flow from the bloodvessel through the bioartificial pancreas; diffusing oxygen from theblood into the cellular complex to maintain a minimum oxygenconcentration of 0.05 mM at the pancreatic islets; diffusing glucosefrom the blood into the cellular complex; generating insulin with thepancreatic islets in response to levels of glucose diffused from theblood into the cellular complex; and delivering insulin generated by thepancreatic islets to the blood. In some embodiments, the implanting stepincludes the step of delivering the bioartificial pancreas through acatheter to the implantation site in the blood vessel and expanding thebioartificial pancreas from a delivery configuration to a deployedconfiguration.

These and other features and advantages are described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

Novel features of embodiments described herein are set forth withparticularity in the appended claims. A better understanding of thefeatures and advantages of the embodiments may be obtained by referenceto the following detailed description that sets forth illustrativeembodiments and the accompanying drawings.

FIGS. 1A and 1B illustrate a bioartificial implant in a blood vessel;FIG. 1A shows perspective view of a partial section view of thebioartificial implant in the blood vessel; and FIG. 1B shows an axialcross section view of the bioartificial implant in the blood vessel.

FIGS. 2A and 2B illustrate axial cross section views of a blood vesselundergoing re-endothelialization over a bioartificial implant.

FIGS. 3A and 3B illustrate another variation of a bioartificial implanthaving one or more layers of a semipermeable membrane; FIG. 3A shows alongitudinal section view of the bioartificial implant; and FIG. 3Bshows an axial cross-sectional view of the bioartificial implant.

FIGS. 4A-4C illustrate a bioartificial implant being placed within ablood vessel using a balloon delivery system.

FIG. 5 illustrates a flowchart indicating a process for forming abioartificial implant.

FIG. 6A shows an elevational view of a cellular complex supportaccording to embodiments of the invention.

FIG. 6B shows a cross-section of the cellular complex support of FIG. 6Ataken along the line 6B-6B in FIG. 6A.

FIG. 7 shows an elevational view of a portion of the cellular complexsupport of FIG. 6A with filling tubes to be disposed within pockets ofthe cellular complex support.

FIG. 8 shows a flat elevational view of a scaffold to which a cellularcomplex support may be attached.

FIG. 9 shows a flat elevational view of the cellular complex support ofFIG. 6A attached to the scaffold of FIG. 8.

FIGS. 10A and 10B show end views of a bioartificial pancreas accordingto an embodiment of this invention in delivery and deployedconfigurations, respectively.

FIGS. 11A and 11B show end views of a bioartificial pancreas accordingto another embodiment of this invention in delivery and deployedconfigurations, respectively.

FIGS. 12A and 12B show end views of a bioartificial pancreas accordingto still another embodiment of this invention in delivery and deployedconfigurations, respectively.

DETAILED DESCRIPTION

Disclosed herein are bioartificial implants, such as bioartificialpancreas implants, that may be implanted into a patient's body forreleasing one or more hormones into the patient's blood stream and formodulating the patient's endocrine system. The implant can be placedinto the blood vessel and reside adjacent to or become incorporatedwithin the blood vessel wall. The implant can include living cells, suchas pancreatic islets, which generate hormones. The proximity of theimplant to the patient's blood stream can provide quick delivery of thehormone(s) to the patient's blood stream and provide goodvascularization for the cells.

FIGS. 1A and 1B illustrate a bioartificial implant 100 within a bloodvessel 102, according to some embodiments. The implant 100 can include ascaffold 104 (such as a stent) and a cellular complex 107 supported bythe scaffold, which includes cells (such as pancreatic islets) and oneor more biocompatible materials. When the implant is within a patient'sblood vessel 102, glucose and oxygen from the flowing blood can reachthe cellular complex 107, which can produce one or more hormones thatmay enter the patient's blood within the lumen 110 of the implant 100and the blood vessel 102, thereby modulating the patient's endocrinesystem. In some cases, the implant 100 is used to treat a disease orcondition, such as metabolic disorders including diabetes, in which caseimplant 100 is a bioartificial pancreas.

The cellular complex can be of any type. In some embodiments thecellular complex can include pancreatic islets such as adult humanislets (either auto or allograft), xenogenic islets (e.g., porcine),embryonic beta cells, islet-like cells differentiated from stem cells,islet-like cells transdifferentiated from other tissue types includingliver and pancreatic acinar cells and pancreatic ductal cells,genetically engineered and/or modified non-beta cells, or anycombination thereof. In some cases, the cellular complex includes celltypes other than pancreatic islets, such as thyroid hormone producingcells and/or adrenal hormone producing cells. The cellular complex mayinclude a combination of pancreatic islets and other cell types. Thetype of cells may depend on the disease or condition and the treatmenthormone(s) for treating such disease or condition. Different types ofcells may be used to generate different type and/or amounts of hormones.In the case of islets, the cells may generate one or more of insulin,amylin, glucagon, somatostatin, ghrelin, and pancreatic polypeptides inany combination and ratio. In some embodiments, the cells are humancells, which may be obtained, for example, from a cell isolationlaboratory. In some embodiments, the cells are animal cells, such asporcine cells. In some cases, the cells are genetically modified cells.In some cases, the implant includes stem cells.

The cellular complex may include cells be embedded within a matrix ofbiocompatible material, which can be configured to sustain the viabilityof the cells. The cells may be encapsulated by the biocompatiblematerial. In some cases, as illustrated in FIG. 1B, the cellular complex107 includes one or more external layers 112 of biocompatible material108 to cover and substantially fully encapsulate the cells 106, therebycreating a barrier between the islet cells and the patient's immuneresponse (e.g., lymphocytes, antibodies, macrophages and/orcomplementary molecules in the blood stream). The biocompatible material108 may be semi-permeable to allow diffusion of nutrients (such asglucose) and/or oxygen across the biocompatible material 108 to reachthe cells 106, and allow hormones and/or waste products from the cells106 to diffuse across the biocompatible material 108 and out of thecellular complex 107. In some cases, the biocompatible material 108 maybe infiltrated with one or more nutrients.

The biocompatible material 108 may be of porous material having anetwork of pores that contain the cells 106. Thus, the cells 106 may bedispersed within a matrix of the biocompatible material 108. In somecases, the cells 106 are in clusters within the matrix of biocompatiblematerial 108. The biocompatible material 108 may be a bio-absorbablematerial, i.e., material that is configured to safely dissolve and/or beabsorbed in the body. In some cases, the biocompatible material 108includes an artificial and/or a natural polymer material. In particularembodiments, the biocompatible material 108 includes an alginate, apolyethylene glycol (PEG), an agarose, polytetrafluoroethylene (PTFE),or any combination thereof, and others. In some embodiments, thebiocompatible material 108 include two or more different types ofpolymers.

The number and concentration of cells within the cellular complex 107 ofthe implant 100 may vary. In some embodiments, the cellular complex 107includes from about 50,000 and one million cells (e.g., islets) (e.g.,from about 50,000 to 100,000, from about 500,000 to one million, or fromabout 100,000 to about one million). In some embodiments, theconcentration (by weight) of cells (e.g., islets) within the cellularcomplex 107 ranges from about 5% to about 100% (e.g., from about 5% to99%, from about 5% to about 90%, from about 50% to about 90%, or fromabout 60% to about 80%).

The biocompatible material 108 may be any material that is notsubstantially harmful or toxic to living cells and/or tissue. Thebiocompatible material 108 may be configured to sustain the viability ofthe islets for a predetermined amount of time. In some instances, thispredetermined amount of time may range from about 3 months to about 5years (e.g., about 6 months to 2 years, about 3 months to 2 years, about1 year to 3 years, or about 9 months to 2 years). According to someembodiments, the biocompatible material 108 includes one or more agentsto help sustain the viability of the cells 106. For example, one or moreenzymes and/or pH regulating agents may be infused or incorporatedwithin the biocompatible material 108 to maintain a hospitableenvironment for the cells 106. In some cases, VEG-A and/or VEG-F is usedto assist with neovascularization. The material 108 can include othercell types such as endothelial and mesenchymal stem cells. The material108 can include extracellular matrix components such as collagen,elastin, fibronectin, laminin, and/or proteoglycans. The material 108may include oxygen radical scavengers and/or oxygen carrying molecules.

The scaffold 104 can have a generally tubular shaped wall with an outersurface defining an outer diameter sufficiently small for residingwithin the blood vessel 102 and an inner surface defining a lumen 110for blood to flow through once the stent is deployed within the vessel102. For instance, the scaffold 104 wall may include a network of strutsseparated by spaces. The struts may be wires or threads that form a meshor web-like structure with openings (also referred to as spaces orholes) between the wires or threads. The scaffold 104 supports thecellular complex 107 (cells 106 and biocompatible material 108). Forexample, at least a portion of the inner surface of the scaffold 104 maybe covered with the cellular matrix 107. In some cases, at least aportion of the outer surface of the scaffold 104 is also (oralternatively) covered with the cellular matrix. In embodiments in whichthe scaffold has struts, the cellular matrix 107 may cover at least aportion of the struts of the scaffold 104. In some cases, the scaffold104 is designed to be radially collapsible and/or expandable.

In some embodiments, the cellular complex 107 covers the scaffold 104such that the cellular complex 107 partially or substantially fullyoccludes some or all of the openings in the scaffold 104 (e.g., betweenthe struts of a stent). In cases in which at least a portion of theopenings between the struts of the scaffold 104 are left open, theseopenings may act as pathways within the walls of the implant 100 toimprove oxygenation of the cells 106 and/or blood vessel 102. In someembodiments, the openings in the scaffold 104 range in size from about0.5 square millimeters (mm²) and 25 mm² (e.g., about 1 to 5 mm², about 5to 25 mm², or about 0.5 to 20 mm²) in area along the walls of theimplant 100. The walls of the implant 100 may include one or moredifferent openings that act as blood flow paths. These additional oralternative blood flow openings may range in size from 100 μm² and10,000 μm² (e.g., about 144 to 10,000 μm², about 1,000 to 5,000 μm², orabout 500 to 9,000 μm²) along the walls of the implant 100.

The scaffold 104 can be made of any suitable material. In someembodiments, the scaffold includes one or more bio-absorbable materialsthat is/are configured to dissolve and/or be absorbed in the body. Insome embodiments, the bio-absorbable material of the scaffold 104includes the same bio-absorbable material as the biocompatible material108 of the cellular complex 107. In some embodiments, the bio-absorbablematerial of the scaffold 104 includes different materials compared tothe biocompatible material 108 of the cellular complex 107. Thebio-absorbable material of the scaffold 104 may include a polymer-basedmaterial, such as one or more of a polylactic acid polymer, a tyrosinepoly carbonate polymer and a salicylic acid polymer. The bio-absorbablematerial of the stent 104 may include a metal-based material, such asone or more of iron, magnesium and zinc. The metal-based material mayinclude one or more metal alloys.

In some variations, the implant 100 includes one or more materials thatare not substantially bio-absorbable. For example, the scaffold 104and/or the biocompatible material 108 may be composed of a material thatthat does not substantially degrade and/or become absorbed by the body.In such cases, the implant 100, or a portion thereof, may be configuredto be retrieved from the patient's blood vessel. For instance, theimplant 100 may be removed from the patient's body after the cells 106are no longer producing sufficient amounts of hormones. In a particularembodiment, the biocompatible material 108 and cells 106 arebio-absorbable and the scaffold 104 is not substantially bio-absorbable(e.g., made of nitinol, titanium, stainless steel, and/ornon-bio-absorbable polymer). Thus, once the biocompatible material 108and cells 106 have been absorbed (or partially absorbed) by the body,the scaffold 104 may be retrieved using, for example, a retrievalcatheter device. In some embodiments, the stent 104 is made of anon-bio-absorbable material.

If the scaffold 104 is made of a bio-absorbable material, thebio-absorbable material may be configured to dissolve and be absorbed inthe body within a predetermined amount of time. The predetermined amountof time can vary depending on a number of factors such as the type ofbio-absorbable material, the size of the scaffold 104 and/or thelocation of the implant 100 within the patient's body. In someembodiments, the resorption rate of the bio-absorbable material of thescaffold 104 may range from about 3 months to about 3 years (e.g., about6 months to 2 years, about 3 months to 2 years, about 1 year to 3 years,or about 9 months to 2 years). In some embodiments, the bio-absorbablematerial of the scaffold 104 is configured to be absorbed in the bodyclose to the time period in which the cells 106 no longer generatehormones. In some embodiments, the bio-absorbable material of thescaffold 104 is configured to be absorbed in the body for a period afterthe cells 106 no longer produce hormones. This may ensure that thebio-absorbable material of the scaffold 104 be present to support thecellular complex, including the cells 106, while they are generatinghormones and at least up until they stop generating hormones. In someembodiments, the bio-absorbable material of the scaffold 104 isconfigured to be absorbed before the cells 106 are no longer generatinghormones. For example, the cells 106 may continue to function within“the pocket” even after the scaffold 104 has been absorbed.

The implant 100 may be placed within any artery or vein of the patient'sbody. In some cases, a preferred location is within an artery so thatthe cellular complex can be exposed to oxygen-rich blood and nutrients.That is, arteries may have higher oxygen tension compared to that ofveins. Further, the blood flow in an artery may confer a relativelyimmune-protected location in the body. Also, veins may have slower bloodflow and lower pressure, making them possibly at higher risk for bloodclots. However, an advantage of placing the implant in a vein is thatthe body may be able to form collateral venous pathways in case the veinbecomes damaged.

In some embodiments, the blood vessel 102 may have a diameter of atleast about 0.5 centimeters (cm). In some embodiments, the blood vesselmay have a diameter ranging from about 0.5 cm to about 4 cm (e.g., about0.5-3 cm, about 1-2 cm, about 1-3 cm, about 2-3 cm, about 1-4 cm, about3-4 cm, about 1.5-3.5 cm, or about 2.5-4 cm).

According to some embodiments, the implant 100 is placed within anartery or a vein in or near the patient's pancreas, spleen, kidneys,liver, heart, and/or other organ. In some cases, the implant 100 isplaced away from a particular organ, or away from organs in general. Insome embodiments, one or more implants 100 may be deployed within one ormore of the splenic artery, splenic vein, celiac artery, iliac artery,infra-renal aorta, thoracic aorta, abdominal aorta, carotid artery,hepatic artery, dorsal pancreatic artery, pancreatica magna artery,transverse pancreatic artery, anterior and posterior superiorpancreatoduodenal artery, anterior and posterior inferiorpancreatoduodenal artery, anterior and posterior superiorpancreatoduodenal vein, and/or anterior and posterior inferiorpancreatoduodenal vein. In some cases, the implant 100 is placed near orin the spleen since the spleen may be considered a non-essential organ.In some cases, the implant 100 placed in the splenic artery may providesome benefits since the splenic artery is relatively long, therebyallowing for deployment of multiple stents and/or a long stent. In somecases, placing the implant 100 in the infra-renal aorta provides somebenefits because the infra-renal aorta may have a relatively largediameter, thereby allowing for a larger diameter stent to support aphysiologic cell volume. Further, the femoral artery may providerelatively easy access to the infra-renal aorta with very minimalin-stent restenosis. In some embodiments, the implant 100 is placed inor near the iliac bifurcation, such as in the infrarenal aorta and/orthe iliac arteries. In some cases, implantation at or near abifurcation, such as the iliac bifurcation, may lower the likelihood ofthe implant 100 travelling within the blood vessel. Also, abdominalaorta and iliac arteries can have relatively large diameters that mayexperience little in-stent restenosis. Other considerations forplacement of the implant 100 can include the likelihood of thrombusformation, the likelihood of an immune reaction, and the shape of theblood vessel (e.g., it may be more difficult to place the implant inwinding blood vessel compared to straight blood vessels). In some cases,two or more implants 100 are placed within the patient's vascularsystem. For example, two or more implants 100 may be deployed within thesame artery, different arteries, the same vein, different veins, or anycombination of arteries and veins.

Once deployed in the patient's blood vessel 102, the implant 100 can beconfigured to contact the inner wall of the blood vessel 102. The outersurface of the implant 100 may have a diameter substantially the same asthe inner diameter of the blood vessel 102. In some cases, the scaffold104 may be configured to withstand the forces generated by the flow ofblood. That is, blood can be allowed to flow through the lumen 110 ofthe scaffold 104 without the scaffold 104 collapsing. The scaffold 104may be configured to withstand radial inward pressure exerted by thewall of the blood vessel 102 without collapsing. In some embodiments,the scaffold 104 can be configured to provide sufficient radial force toeffectively increase a local diameter of the blood vessel lumen. Thismay enable the placement of a stent with an overall larger totaldiameter without occluding the lumen of the blood vessel 102.

In some cases, the scaffold 104 and the biocompatible material 108 mayboth be made of a continuous bio-absorbable material having a tubularshape with cells 106 dispersed therein. The walls of the tubular shapedbio-absorbable material may have a mesh or web-like structure withopenings between struts of the mesh or web-like structure, which may actas blood flow paths for oxygenating the cells 106 and/or blood vessel102, as described herein. In some cases, the walls of the tubular shapedbio-absorbable material have different openings instead of or inaddition to the openings between struts as blood flow paths, asdescribed herein. The walls of the tubular shaped bio-absorbablematerial may be configured to adhere to the inner walls of the bloodvessel 102, thereby leaving the lumen 110 intact for blood to flowtherethrough.

The implant 100 may be designed to operate within the range oftemperatures expected to be encountered while implanted within thepatient's body. That is, the implant can be nominally configured tooperate around an average body temperature (e.g., about 37 degrees C.)and during body temperature fluctuations.

The size of the implant 100 may vary depending, for example, on the sizeof the blood vessel 102. In some embodiments, the implant 100 has alength ranging from about 2 centimeters (cm) and 10 cm (e.g., about 2-3cm, about 3-10 cm, about 5-10 cm, or about 6-10 cm).

In some cases, an endothelial layer grows over the bioartificial implantby a re-endothelialization process. FIGS. 2A and 2B illustrate anexample of blood vessel wall 102 undergoing re-endothelialization overbioartificial implant 100, according to some embodiments. FIG. 2A showsthe implant 100 implanted and functioning to secrete insulin within thelumen 110 of the implant 100 (and the blood vessel 102) in response tochanges in blood glucose. After a period of time, an endothelial celllayer 120 may form over the implant 100, as shown in FIG. 2B. Thisre-endothelialization can create a space, or pocket, between theendothelial cell layer 120 and the blood vessel wall 102 for the implant100 to reside. The cells of the implant 100 can continue to generatehormones (e.g., insulin) that is secreted into the lumen 110 while inthe pocket. The endothelial layer 102 may act as a semi-permeablebarrier that protects the cells 106 from the patient's immune response,and that allows diffusion of nutrients and/or oxygen to the islet cells106 and hormones and/or waste from the cells 106. The endothelial layer102 may be present with or without the one or more external layers 112of biocompatible material 108 as described herein.

The bio-absorbable material of the implant 100 (e.g., scaffold 104and/or biocompatible material 108) can gradually become absorbed by thebody as the cells 106 continue to generate hormones (e.g., insulin).After a period of time, the cells 106 may no longer be able to generatehormones (e.g., insulin), which can be due to the biocompatible material108 becoming absorbed by the body, the natural lifespan of the cells, orboth. Once the implant becomes absorbed and the cells disintegrateand/or cease to secrete hormones (e.g., insulin) within the pocket, anew implant may be deployed within the blood vessel 102.

According to some embodiments, the bioartificial implant may be modifiedto include one or more chemical agents (e.g., small molecules, drugs,and/or proteins). For example, the implant 100 may include a growthfactor, such as vascular endothelial growth factor (e.g., VEG-A and/orVEG-F) to promote growth of endothelial cells. The implant 100 mayinclude an anticoagulant, such as heparin. Additional or alternativechemical agents can include anti-inflammatory drugs such as TNF alphainhibitors and/or immune-suppression medications such as sirolimus ortacrolimus. The chemical agents may be coated onto or incorporatedwithin the biocompatible material 108 of the cellular complex and/or thescaffold 104. According to some embodiments, the implant 100 can includeone or more additional types of cells other than pancreatic islet cells.For example, follicular cells may be incorporated in the cellularcomplex 108 to release thyroid hormones (e.g., thyroid T4/T3) or otheragents for modulating the endocrine system. The cellular complex 108 mayinclude cells that produce parathyroid hormone (PTH) and/or adrenalgland hormones (e.g., cortisol and/or aldosterone) and/or sex hormones.In some cases, the implant 100 includes stem cells.

The implant may be delivered within the patient using any method. Insome cases, the implant is delivered into the blood vessel using acatheterization procedure. As described herein, the implant can becollapsible and expandable. Thus, in some embodiments, the implant canbe deployed intravascularly using endovascular techniques. One suchtechnique involves a balloon delivery system.

FIGS. 3A and 3B show a variation of the implant 100 where one or morelayers of semipermeable material that surround the scaffold 104, thecellular complex 107, and the cells 106. FIG. 3A shows a longitudinalsection view of the implant 100, and FIG. 3B shows an axialcross-sectional view of the implant 100. One or more layers 320 of asemipermeable membrane can be used to encase the scaffold 104 and thecellular complex 107. That is, the one or more layers 320 can cover aninner diameter 350 of the scaffold and the outer diameter 352 of thescaffold. The cellular complex 107 can be infused between the layer(s)320. The layer(s) 320 of semipermeable membrane may be made of anybiocompatible material that can substantially prevent exposure of thecells to the patient's immune response while also allowing permeation ofhormones, oxygen, nutrients, and waste products to and from the cells inthe cellular complex. In some embodiments, the layer(s) 320 ofsemipermeable membrane are made of a natural polymer and/or a syntheticpolymer (e.g., PTFE). In some cases, the layer(s) 320 include two sheetsof semipermeable material that are sealed together at a proximal end 340and a distal end 342 of the implant 100. In some embodiments, the twosheets of semipermeable material are sealed together (e.g., via heatmolding). In some embodiments, a sealant 360 is used to seal the twosheets of semipermeable material together. The sealant 360 may be madeof any biocompatible material that can maintain a seal while within thepatient's blood vessel. In some embodiments, the sealant 360 can bebiocompatible glue and/or a biocompatible chemical sealant.

FIGS. 4A-4C illustrate an example of a bioartificial implant beingplaced within a blood vessel using a balloon delivery system. Theballoon delivery system can include an inflatable balloon 450 and aguidewire 452. Before insertion into the blood vessel, the implant 100can be mounted around the balloon 450 while the balloon 450 is in adeflated state and the stent of the implant 100 is in a collapsed state.The implant 100 may be manufactured on the balloon 450 or loaded ontothe balloon 450 after manufacturing. FIG. 4A shows the balloon 450 withthe implant 100 being guided through the lumen of the blood vessel 102with the aid of the guidewire 452. The access site for insertion of thedelivery system can vary depending on the target blood vessel and thetarget location within the target blood vessel. In some cases, theaccess site is an artery, such as a femoral or radial artery.

Once a target location within the blood vessel 102 is reached, theballoon 102 can be inflated so that it expands within the blood vessel102, as shown in FIG. 4B. The expansion of the balloon 102 can cause theimplant 100 to expand from its collapsed state to an expanded state andto contact the inner surfaces of the blood vessel 102. In some cases,the implant 100 is deployed to a fully expanded state, or nearly a fullyexpanded state. After the implant 100 is expanded, the balloon 450 canbe deflated and removed from the vessel 102 using the guidewire 452.

In some embodiments, one or more radio-opaque markers may be used tovisualize the delivery system and/or the implant 100 during deliveryinto the patient. For example, ring-shaped markers may be positioned ator near the ends of the implant 100 so that the doctor can view themarkers using a radio frequency imaging techniques and deduce thelocation of the implant 100 during the procedure. The radio-opaquemarker(s) may be removable from the delivery system and/or the implant100 and the patient once the implant 100 is placed in the patient.

In other embodiments, the implant 100 is configured to be implantedwithin the blood vessel 102 without the use of a balloon. For example,the scaffold 104 (FIGS. 1A-3B) may be a self-expandable stent. In aparticular variation, the self-expandable stent may be compressed withina delivery catheter and positioned within the blood vessel 102. An outersheath of the delivery catheter can be retracted to allow theself-expandable stent to expand in a spring-like fashion to achieve adesired expansion diameter at the target location within the bloodvessel 102.

The bioartificial implants described herein can be manufactured usingany of a number of different techniques. FIG. 5 illustrates a flowchartindicating a process for forming a bioartificial implant, according tosome embodiments. A cellular complex can be formed (502), for example,by combining the cells with one or more biocompatible materials, whichmay also optionally be bio-absorbable. In particular embodiments, thebiocompatible material may include an alginate, a PEG, an agarose,and/or a collagen polymer. The islet cells may be mixed with thebiocompatible polymer(s) in a solution (e.g., aqueous solution) to forma slurry. In some embodiments, one or more chemical agents (e.g., drugs)and/or non-islet cells are added to the slurry to incorporate thechemical agents and/or non-islet cells into the cellular complex.

A scaffold that is designed to be inserted within a patient's bloodvessel (e.g., a stent) can be coated with the cellular complex (504).The scaffold may be made of a bio-absorbable material and/orbiocompatible material, such as a bio-absorbable polymer or metal stent.In some cases, the scaffold is pretreated with one or more chemicalagents to promote adhesion of the cellular complex to the stent. Suchagents may include one or more peptide coatings. For example, anintegrin binding motif, such as the RGD motif (arginine-glycine-asparticacid peptide), can be used to promote cellular adhesion to the scaffold.In some cases, one or more layers of biocompatible materials are used tocoat the scaffold. In some embodiments, the scaffold includes one ormore chemical agents (e.g., drugs) so that the scaffold may elute thechemical agent(s) while in the patient's body. The chemical agent(s) maybe coated on the stent and/or incorporated within the material of thescaffold. Any of a number of coating methods may be used. In someembodiments, the cellular complex is deposited using a liquid depositionprocess, an ultrasonic coating process, a spray deposition process, orany combination thereof. In some embodiments, the cellular complex isdeposited as a solution (e.g., aqueous solution). Once deposited, thesolution with cellular complex may be allowed to dry to some degree. Insome cases, the solution with cellular complex may be kept in solution(e.g., wet).

In some embodiments, the cellular complex on the scaffold may optionallybe coated with one or more layers of biocompatible material (506). Thebiocompatible coating may serve to encapsulate the cells of the cellularcomplex from being eroded away from the scaffold due to exposure toflowing blood in the patient's blood stream while permitting oxygen andglucose to reach the cells and permitting waste products to leave thecells. Each of the layers of biocompatible coating may be very thin,e.g., ranging from about one nanometer to about one millimeter. Thetotal thickness of the biocompatible coating may range from about onenanometer to about five millimeters.

FIGS. 6A-9 show an embodiment of a bioartificial pancreas 600. Cellularcomplex 602 made up of pancreatic islets and biocompatible material isdisposed in pockets 604 of a cellular complex support 606. Inembodiments, cellular complex 602 may have an islet density of 2.5% to100%, or an islet density of 12% to 30%. In embodiments in which theislet density is less than 100%, the remainder of the cellular complexmay be a porous medium, such as one or more of alginate, agarose, PEG,chitosan, etc.

To maintain the viability of the islets when the bioartificial pancreasis implanted within a blood vessel, and to enable the bioartificialpancreas to perform its function of releasing insulin in response toblood glucose levels, oxygen and glucose from the blood flowing throughthe device (and possibly from the vasa vasorum capillary network in theblood vessel wall) must reach the islets in the bioartificial pancreas.The higher the blood glucose level, the greater the oxygen consumptionby the islets. The bioartificial pancreas implants of this inventiontherefore provide a structure than enables oxygen and glucose to diffusefrom flowing blood into the cellular complex at a rate sufficient tosupport the viability of the islets. The devices also provide an isletdensity within the cellular complex no greater than that which can besupported by levels of oxygen reaching the islets and which can performthe function of supplying adequate amounts insulin in response toglucose reaching the islets within the cellular complex. In theembodiments described herein, oxygen reaches all of the islets in thecellular complex through the cellular complex support at a minimumconcentration of 0.05 mM O₂.

In this embodiment, cellular complex support 606 has two layers 608 and610 of a microporous thin film bordering the pockets 604. Layers 608 and610 are attached to each other at the outer edges of cellular complexsupport 602 and in attachment regions 612 adjacent pockets 604. Cellularcomplex 602 is disposed in pockets 604. In embodiments, each layer ofthe thin film has a thickness less than 0.1 mm. In embodiments, the thinfilm layers can have pores with diameters less than 100 μm in order toenable glucose and oxygen in blood flowing through the scaffold to enterthe pockets 604 to reach the cellular complex 602 at a rate sufficientto support the viability of the islets and to enable insulin produced bythe islets in the cellular complex to reach the flowing blood. The poresmay also permit glucose and/or oxygen to reach the cellular complex fromvasa vasorum capillaries of the blood vessel in which the bioartificialpancreas 600 is implanted. Placement of the bioartificial pancreas in ablood vessel may result in angiogenesis of the vasa vasorum capillarynetwork in that blood vessel. In embodiments, the thickness T of theassembled cellular complex support may be from 0.30 mm to 1.0 mm,inclusive, as shown in FIG. 6B.

In embodiments of the invention, the two layers 608 and 610 of cellularcomplex support 606 may be polymer, such as ePTFE, hydrophilic ePTFE,nylon, polyethylene or PEEK. To thermally bond the layers 608 and 610, abinding agent (e.g., FEP or polyurethane) may be applied to a topsurface of layer 608 at the sites of the attachment regions 612 andaround the outer edges 618 of layer 608. A small tube 620 (e.g., a300-500 μm diameter polyethylene tube) may be placed on the top side oflayer 608 at the sites of each pocket 604, with an open end of each tube620 at one end of the pocket and a portion of each tube 620 extendingbeyond the border of layer 608, as shown in FIG. 7. A bottom side of thesecond layer 610 may then be placed on the top side of layer 608 andover the tubes 620. An oven or a sealing device may then be used to heatthe layers and bonding agent (e.g., at 200° F.-500° F.) to thermallybond the layers to each other at the attachment regions 612 and theouter edges 618 of the cellular complex support 606.

Other embodiments forego the use of a binding agent and rely on asufficiently low melting point of the polymer from which layers 608 and610 are formed. Heat applied to the bottom surface of layer 608 and thetop surface of layer 610 at the attachment regions 612 and/or outeredges 618 will melt the polymer locally. The polymer will thenresolidify to form welds at the attachment regions 612 and/or edges 618.

In one optional preparation method for cellular complex 602 and cellularcomplex support 606, islets are mixed at 37° C. with a microporoushydrogel (e.g., alginate, fibrin, chitosan, agarose, polyethyleneglycol) at an islet density of 12%-30%, and a polymer crosslinker isadded to harden the hydrogel to provide greater mechanical stability forprotection of the islets. A Hamilton syringe may be used to inject thecellular complex into pockets 604 via tubes 620. Each tube 620 may beslowly withdrawn from its pocket 604 as the cellular complex is injectedto ensure even distribution of the cellular complex in the pocket. Aftercellular complex injection is complete and tubes 620 have been withdrawnfrom pockets 604, the outer edges of each pocket 604 may be heat sealedin the manner described above to close the pockets and to prevent theescape of any cellular complex. After sealing pockets 604, the cellularcomplex support may be cooled at room temperature (i.e., 4° C.). Thecellular complex 602 may be injected into the cellular complex support606 before or after attaching the cellular complex support to thescaffold.

The bioartificial pancreas 600 may be configured as a cylinder orportion of a cylinder so as to rest against the inner wall of a bloodvessel, such as the descending aorta. FIGS. 8 and 9 show scaffold 614and cellular complex support 606 in a flat configuration, however, forpurposes of illustration. In this embodiment, scaffold 614 is acylindrical mesh stent surrounding an internal cavity. Scaffold 614 maybe formed from, e.g., a shape-memory alloy such as Nitinol, or it may beformed from a bio-absorbable material. Scaffold 614 can be compressedfor delivery and expanded (e.g., by self-expansion) for deployment in apatient's blood vessel, such as the descending aorta. The attachmentregions 612 and/or outer edges 618 of the cellular complex support 606can be attached to the filaments 616 of the scaffold 614 via a thermalbond, pressure bond, sutures, glue, or any other suitable attachmentmechanism. In this embodiment, the cellular complex support 606substantially surrounds the entire inner cavity of the scaffold. Inother embodiments, the cellular complex support borders only a portionof the interior cavity of the scaffold.

In embodiments, one or both of the thin film layers can have one or moreof the following on outside surfaces: a hydrogel, heparin, growthfactors (e.g., VEGF, VEGA), and immunotherapy substances (e.g.,sirolimus, tacrolimus).

The bioartificial pancreas of this invention may be delivered via acatheter to the desired implantation site within a blood vessel, such asthe infrarenal aorta. The bioartificial pancreas may have a smallerdiameter delivery configuration and a larger diameter deployedconfiguration. The bioartificial pancreas may have a diameter of 1-10 mmin the delivery configuration and a diameter of 5 mm-25 mm in thedeployed configuration.

FIGS. 10A-B illustrate delivery and deployment configurations of abioartificial pancreas 700 according to one embodiment of the invention.As in embodiments described above, bioartificial pancreas 700 has acellular complex support 706 attached to a scaffold 714. Cellularcomplex, such as islets and a microporous hydrogel, as described above,is loaded into cellular complex support 706. As shown in FIG. 10A, thebioartificial pancreas 700 is loaded into a delivery catheter 730 in asmaller diameter delivery configuration such that the pockets 704containing the cellular complex extend radially inward while theattachment regions 712 remain attached to scaffold 714. Protrusions 732on the inner surface of catheter 730 engage outer surfaces of thescaffold 714, such as at scaffold struts 734. When the bioartificialpancreas 700 emerges from the distal end of the catheter at the desiredimplantation site in the blood vessel 736, scaffold 714 self-expands andpockets 704 move radially outward. FIGS. 10A-B are not necessarily drawnto scale.

FIGS. 11A-B illustrate delivery and deployment configurations of abioartificial pancreas 800 according to another embodiment of theinvention. As in embodiments described above, bioartificial pancreas 800has a cellular complex support 806 attached to a scaffold 814, andcellular complex, such as islets and a microporous hydrogel, asdescribed above, is loaded into cellular complex support 806. In thisembodiment, the cellular complex support 806 covers a smaller portion ofthe inside surface area of scaffold 814 compared to other embodiments,and instead of being a closed cylinder, the scaffold 814 has open edges838 and 840. As shown in FIG. 11A, the bioartificial pancreas 800 isloaded into a delivery catheter 830 in a smaller diameter deliveryconfiguration by rolling scaffold 814 into a spiral. When thebioartificial pancreas 800 emerges from the distal end of the catheterat the desired implantation site in the blood vessel 836, scaffold 814self-expands by unwinding the spiral. FIG. 11B shows scaffold 816unwound such that the open edges substantially meet. Depending on thediameter of blood vessel 836, however, the open edges 838 and 840 ofscaffold 814 may be separated, forming an open cylinder or tube, or theopen edges 838 and 840 may still overlap somewhat, forming part of aspiral. FIGS. 11A-B are not necessarily drawn to scale.

FIGS. 12A-B illustrate delivery and deployment configurations of abioartificial pancreas 900 according to yet another embodiment of theinvention. As in embodiments described above, bioartificial pancreas 900has a cellular complex support 906 attached to a scaffold 914. Cellularcomplex, such as islets and a microporous hydrogel, as described above,is loaded into cellular complex support 906. As shown in FIG. 12A, thebioartificial pancreas 900 is loaded into a delivery catheter 930 in asmaller diameter delivery configuration such that the cellular complexsupport 906 and scaffold 914 form radially inward folding portions 938.When the bioartificial pancreas 900 emerges from the distal end of thecatheter at the desired implantation site in the blood vessel 936,scaffold 914 self-expands to substantially eliminate folding portions938, as shown in FIG. 12B. FIGS. 12A-B are not necessarily drawn toscale.

In some embodiments, the stent and/or the cellular complex ismanufactured using a three-dimensional (3D) printing process. In somecases, the entire implant, including the stent and/or the cellularcomplex is manufactured using a 3D printing process.

When a feature or element is herein referred to as being “on” anotherfeature or element, it can be directly on the other feature or elementor intervening features and/or elements may also be present. Incontrast, when a feature or element is referred to as being “directlyon” another feature or element, there are no intervening features orelements present. It will also be understood that, when a feature orelement is referred to as being “connected”, “attached” or “coupled” toanother feature or element, it can be directly connected, attached orcoupled to the other feature or element or intervening features orelements may be present. In contrast, when a feature or element isreferred to as being “directly connected”, “directly attached” or“directly coupled” to another feature or element, there are nointervening features or elements present. Although described or shownwith respect to one embodiment, the features and elements so describedor shown can apply to other embodiments. It will also be appreciated bythose of skill in the art that references to a structure or feature thatis disposed “adjacent” another feature may have portions that overlap orunderlie the adjacent feature.

Terminology used herein is for the purpose of describing particularembodiments only and is not intended to be limiting of the invention.For example, as used herein, the singular forms “a”, “an” and “the” areintended to include the plural forms as well, unless the context clearlyindicates otherwise. It will be further understood that the terms“comprises” and/or “comprising,” when used in this specification,specify the presence of stated features, steps, operations, elements,and/or components, but do not preclude the presence or addition of oneor more other features, steps, operations, elements, components, and/orgroups thereof. As used herein, the term “and/or” includes any and allcombinations of one or more of the associated listed items and may beabbreviated as “/”.

Spatially relative terms, such as “under”, “below”, “lower”, “over”,“upper” and the like, may be used herein for ease of description todescribe one element or feature's relationship to another element(s) orfeature(s) as illustrated in the figures. It will be understood that thespatially relative terms are intended to encompass differentorientations of the device in use or operation in addition to theorientation depicted in the figures. For example, if a device in thefigures is inverted, elements described as “under” or “beneath” otherelements or features would then be oriented “over” the other elements orfeatures. Thus, the exemplary term “under” can encompass both anorientation of over and under. The device may be otherwise oriented(rotated 90 degrees or at other orientations) and the spatially relativedescriptors used herein interpreted accordingly. Similarly, the terms“upwardly”, “downwardly”, “vertical”, “horizontal” and the like are usedherein for the purpose of explanation only unless specifically indicatedotherwise.

Although the terms “first” and “second” may be used herein to describevarious features/elements (including steps), these features/elementsshould not be limited by these terms, unless the context indicatesotherwise. These terms may be used to distinguish one feature/elementfrom another feature/element. Thus, a first feature/element discussedbelow could be termed a second feature/element, and similarly, a secondfeature/element discussed below could be termed a first feature/elementwithout departing from the teachings of the present invention.

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising” means various components can be co-jointlyemployed in the methods and articles (e.g., compositions and apparatusesincluding device and methods). For example, the term “comprising” willbe understood to imply the inclusion of any stated elements or steps butnot the exclusion of any other elements or steps.

In general, any of the apparatuses and methods described herein shouldbe understood to be inclusive, but all or a sub-set of the componentsand/or steps may alternatively be exclusive, and may be expressed as“consisting of” or alternatively “consisting essentially of” the variouscomponents, steps, sub-components or sub-steps.

As used herein in the specification and claims, including as used in theexamples and unless otherwise expressly specified, all numbers may beread as if prefaced by the word “about” or “approximately,” even if theterm does not expressly appear. The phrase “about” or “approximately”may be used when describing magnitude and/or position to indicate thatthe value and/or position described is within a reasonable expectedrange of values and/or positions. For example, a numeric value may havea value that is +/−0.1% of the stated value (or range of values), +/−1%of the stated value (or range of values), +/−2% of the stated value (orrange of values), +/−5% of the stated value (or range of values), +/−10%of the stated value (or range of values), etc. Any numerical valuesgiven herein should also be understood to include about or approximatelythat value, unless the context indicates otherwise. For example, if thevalue “10” is disclosed, then “about 10” is also disclosed. Anynumerical range recited herein is intended to include all sub-rangessubsumed therein. It is also understood that when a value is disclosedthat “less than or equal to” the value, “greater than or equal to thevalue” and possible ranges between values are also disclosed, asappropriately understood by the skilled artisan. For example, if thevalue “X” is disclosed the “less than or equal to X” as well as “greaterthan or equal to X” (e.g., where X is a numerical value) is alsodisclosed. It is also understood that the throughout the application,data is provided in a number of different formats, and that this data,represents endpoints and starting points, and ranges for any combinationof the data points. For example, if a particular data point “10” and aparticular data point “15” are disclosed, it is understood that greaterthan, greater than or equal to, less than, less than or equal to, andequal to 10 and 15 are considered disclosed as well as between 10 and15. It is also understood that each unit between two particular unitsare also disclosed. For example, if 10 and 15 are disclosed, then 11,12, 13, and 14 are also disclosed.

Although various illustrative embodiments are described above, any of anumber of changes may be made to various embodiments without departingfrom the scope of the invention as described by the claims. For example,the order in which various described method steps are performed mayoften be changed in alternative embodiments, and in other alternativeembodiments one or more method steps may be skipped altogether. Optionalfeatures of various device and system embodiments may be included insome embodiments and not in others. Therefore, the foregoing descriptionis provided primarily for exemplary purposes and should not beinterpreted to limit the scope of the invention as it is set forth inthe claims.

The examples and illustrations included herein show, by way ofillustration and not of limitation, specific embodiments in which thesubject matter may be practiced. As mentioned, other embodiments may beutilized and derived there from, such that structural and logicalsubstitutions and changes may be made without departing from the scopeof this disclosure. Such embodiments of the inventive subject matter maybe referred to herein individually or collectively by the term“invention” merely for convenience and without intending to voluntarilylimit the scope of this application to any single invention or inventiveconcept, if more than one is, in fact, disclosed. Thus, althoughspecific embodiments have been illustrated and described herein, anyarrangement calculated to achieve the same purpose may be substitutedfor the specific embodiments shown. This disclosure is intended to coverany and all adaptations or variations of various embodiments.Combinations of the above embodiments, and other embodiments notspecifically described herein, will be apparent to those of skill in theart upon reviewing the above description.

1. A bioartificial pancreas comprising: a scaffold configured to engagean interior wall of a blood vessel, the scaffold comprising a blood flowlumen extending longitudinally through an interior cavity of thescaffold so as to permit blood flow therethrough when the scaffold isengaged with the blood vessel; a cellular complex support supported bythe scaffold and extending longitudinally within the interior cavity ofthe scaffold so as to be exposed to the blood flow when the scaffold isengaged with the blood vessel, the cellular complex support comprisingone or more pockets bordered by thin film; and a cellular complexcomprising pancreatic islet cells disposed in the one or more pockets,the thin film being configured to permit nutrients to diffuse fromflowing blood into the one or more pockets at a rate sufficient tosupport the viability of the islets. 2-106. (canceled)
 107. Thebioartificial pancreas of claim 1, wherein the cellular complex supporthas a thickness from 0.30 mm to 1.0 mm when loaded with the cellularcomplex.
 108. The bioartificial pancreas of claim 1 wherein the cellularcomplex support further comprises at least one attachment regionadjacent to the one or more pockets, the cellular complex support beingattached to the scaffold at the at least one attachment region.
 109. Thebioartificial pancreas of claim 108, further comprising a thermal bondbetween the at least one attachment region and the scaffold attachingthe cellular complex support to the scaffold.
 110. The bioartificialpancreas of claim 108, further comprising a suture attaching the atleast one attachment region of the cellular complex support to thescaffold.
 111. The bioartificial pancreas of claim 107, furthercomprising a pressure bond between the at least one attachment regionand the scaffold, which attaches the cellular complex support to thescaffold.
 112. The bioartificial pancreas of claim 1, wherein thecellular complex support comprises two microporous thin film layersbordering the pockets.
 113. The bioartificial pancreas of claim 112,wherein each microporous layer has a plurality of pores each having adiameter of less than 100 μm.
 114. The bioartificial pancreas of claim112, wherein each microporous layer has a thickness of less than 0.1 mm.115. The bioartificial pancreas of claim 1, wherein the cellular complexcomprises 2.5% to 100% pancreatic islet cells.
 116. The bioartificialpancreas of claim 115, wherein the cellular complex comprises 12% to 30%pancreatic islet cells.
 117. The bioartificial pancreas of claim 1,wherein the cellular complex support extends substantially around theinterior cavity.
 118. The bioartificial pancreas of claim 1, wherein thecellular complex support extends only partially around the interiorcavity.
 119. The bioartificial pancreas of claim 1, wherein the scaffoldis an expandable stent.
 120. The bioartificial pancreas of claim 119,wherein the cellular complex support is attached to struts of theexpandable stent.
 121. The bioartificial pancreas of claim 1, whereinthe scaffold and cellular complex support have a delivery configurationwith a first diameter and a deployed configuration with a seconddiameter greater than the first diameter, wherein the bioartificialpancreas is configured to be delivered to said subject in the deliveryconfiguration by a catheter to an implantation site within the bloodvessel of said subject and to be expanded to the deployed configurationoutside of the catheter at the implantation site.
 122. The bioartificialpancreas of claim 1, wherein the scaffold is bio-absorbable.
 123. Thebioartificial pancreas of claim 1, wherein said subject is human. 124.The bioartificial pancreas of claim 1, wherein said pancreatic isletcells are human pancreatic islet cells.
 125. The bioartificial pancreasof claim 123, wherein said pancreatic islet cells are human pancreaticislet cells.